This document discusses intravenous (IV) fluid choice from an intensive care perspective. It begins by introducing IV fluids as a cornerstone treatment in emergency and intensive care medicine and discusses the debate around the relative safety of different IV fluid formulations. It summarizes the findings of several large randomized controlled trials that compared colloids to crystalloids and found increased risks of harm with some colloids. The document analyzes the safety of different IV fluid options like albumin, hydroxyethyl starches, and crystalloids based on evidence from major trials. It concludes that normal saline is generally the default fluid but that more physiological crystalloids may be preferable in some situations like burns or metabolic acidosis.

1. IV Fluid Choice - an ICU
perspective
(With 2 Cautionary stories about Cochrane
Meta-analysis)
Dr Vincent Chan
Senior Registrar in Emergency and Intensive Care Medicine
17th
April 2014

2. Introduction
• Iv fluids are a cornerstone treatment
of emergency and intensive care
medicine
• There are numerous varieties of iv
fluids however their relative safety is
under debate particularly with
colloids
• 2 Cochrane meta-analyses
demonstrated increased risk of harm
with IV albumin and no increase in
harm with IV Hydroxyethyl starches
compared with crystalloids
• 3 Large randomised Control trials in
Australian, New Zealand and
Scandinavian intensive cares units
have proved Cochrane wrong

3. Crystalloid, Colloid and Blood Products
• Strictly speaking IV fluids include Crystalloid Colloid and Blood
• This talk will be confined to Crystalloids and Colloids
• Use of blood products and transfusion triggers deserve a separate
discussion in itself

4. Crystalloid and Colloids
• Crystalloids are predominately based
on a solution of sterile water with
added electrolytes to approximate the
mineral content of human plasma.
• Colloids are often based on crystalloid
solutions, thus containing water and
electrolytes, but have the added
component of a colloidal substance
that does not freely diffuse across a
semipermeable membrane
• Colloids can raise the intravascular
volume quicker and using less volume
than using crystalloids

5. Variations in Colloids and Crystalloids
Formulations
Solution pH Na+ Cl- K+ Ca++ Lactate Glucose Osmolality Other
0.9% normal saline 5.0 154 154 0 0 0 0 308 0
Hartmann/CSL 5-7 131 112 5 2 28 0 255 0
Plasma lyte 7.4 140 98 5 0 0 0 294 27mmol Acetate 23mmol Gluconate
5% dextrose in water (D5W) 4.0 0 0 0 0 0 50 g/L 252 0
.45% normal saline with
dextrose (D51/2 NS) 4.5 77 77 0 0 0 50 g/L 406 0
Albumin (4%) 6.7-7.3 140 128 0 0 0 0 260 40 g/L albumin
Albumin (20%) 6.4-7.3 48-100 130-160 0 0 0 0 130 200 g/L albumin
Hetastarch 6% 5.5 154 154 0 0 0 0 310 60 g/L starch
Pentastarch 10% 5.0 154 154 0 0 0 0 326 100 g/L starch
Dextran-40
(10% solution) 3.5-7.0 154 154 0 0 0 0 311 100 g/L dextran
Dextran-70
(6% solution) 3.0-7.0 154 154 0 0 0 0 310 60 g/L dextran
Haemaccel 3.5% 7.4 145 145 5 6.25 0 0 293 35 g/L gelatin
Gelofusine 7.4 154 125 0 0 0 0 308 40 g/L gelatin

6. Safety of Colloids
• It has been assumed over the past 60 years that both colloids and crystalloids are safe
and effective means of intravenous fluid resuscitation
• The safety of colloids was first questioned by a rudimentary meta-analysis performed by
Velanovich in 1989. (1)
• Subsequently in the BMJ in 1998 a systematic review questioned the safety of colloids in
general[2] and a Cochrane Review in 1998, questioned specifically the safety of albumin.
[3]
• This can only be resolved by a large randomised control trial
1. Velanovich V. Crystalloid versus colloid fluid resuscitation: a meta-analysis of mortality. Surgery.
1989;105:65-71
2. Schierhout G, Roberts I. Fluid resuscitation with colloid or crystalloid solutions in critically ill
patients: a systematic review of randomized trials. BMJ. 1998;316:961-964.
3. Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill
patients: systematic review of randomised controlled trials. BMJ. 1998;317:235-240

7. The SAFE (Saline versus Albumin Fluid
Evaluation) trial
• Conducted by the Australia and New Zealand Intensive Care Society's
Clinical Trials Group (ANZICS-CTG) between 2001 and 2003
• Published NEJM May 2004
• Double blind prospective multi-centre randomised controlled trial
• Determine the effect of fluid resuscitation with either 4% Albumin or
N/saline on mortality in a heterogeneous population of Intensive care
Patients
• Excluded patients – Burns, plasmapheresis, cardiac bypass surgery and
liver transplant
• Randomized 6997 critically ill patients requiring fluid resuscitation to
receive 4% albumin or Normal Saline

8. The SAFE (Saline versus Albumin Fluid
Evaluation) trial
• There was no overall difference in outcome according to whether
patients received colloids or crystalloids (relative risk for death with
colloid use = .99, 95% confidence interval .91-1.09, P = .87).
• Prospective Subgroup Analysis
• Trauma Patients appeared to be more likely to die if they received colloids
and this was statistically true for those patients with traumatic brain injury
compared with trauma patients as a whole (relative risk for death = 1.62, 95%
confidence interval 1.12-2.34, P = .009).
• Severe Sepsis trends toward a reduction in death for who received colloids
(relative risk = .87, 95% confidence interval .74-1.02).
• ARDS no statistically significant difference

9. Subgroups Identified in the Saline vs
Albumin Fluid Evaluation Study
Outcome Albumin Saline RR (95% CI) P Value
Trauma 13.6% 10.0% 1.36 (.99-1.86) .06
(81 of 596) (59 of 590)
Severe sepsis 30.7% 35.3% .87 (.74-1.02) .09
(185 of 603) (217 of 615)
ARDS 39.3% 42.4% .93 (.61-1.41) .72
(24 of 61) (28 of 66)

10. Hydroxyethyl Starch
• Derived from Maize Starch
• Hydrolysed amylopectin in the C2 C3 and
C6 units of the macromolecules
• Eliminated only through the kidneys as
the products of endogenous hydrolysis
• C2 units impairs hydrolysis more
effectively than one in position C6
• Charactered by
• mean molecular weight in Daltons
• C2/C6 ratio
• Voluven and Volulyte
• New generation low molecular weight and
low C2/C6 Ratio HES 130/0.42
• Most commonly used colloid in intensive
care units globally

11. The Boldt Affair
• Joachim Boldt MD PHD
• Chief Anaesthetist at Ludwigshafen Hospital in Rhineland Germany
• Leading Advocate of Hyroxyethyl starch (HES)
• Prolific submitting on average 1 paper a month
• 11 papers demonstrated a relative reduction in mortality with HES
• Some have been cited in manufacturers product information sheets, submissions to
regulatory authorities, clinical trial protocols and Meta-analysis.
• Cochrane review in 2007 with regards to Colloids versus crystalloids for fluid
resuscitation in critically ill patients analysed 55 studies concluded that there was no
significant difference
• Discovered in 2011 to have published 101 articles of which 89 papers did not have
institutional review board approval
• Lead to dismissal from post, multiple article retractions and ongoing criminal
investigations

12. THE 6S Trial: Hydroxyethyl Starch 130/0.42
versus Ringer's Acetate in Severe Sepsis
• Published NEJM July 2012
• 6S trial Group Scandinavian Critical Care Trials Group
• Multicentre parallel group blinded clinical trial
• Conducted between 2009 and 2011 in Denmark, Norway, Finland and
Iceland
• To assess the effect of HES 130/0.4 compared with a balanced crystalloid
solution on mortality and end stage kidney failure in patients with severe
sepsis.
• 798 patients with Severe Sepsis
• 398 randomised to HES 130/0.42 for fluid resuscitation
• 400 randomised to Ringers Acetate group

13. The 6S Trial: Hydroxyethyl Starch 130/0.42
versus Ringer's Acetate in Severe Sepsis
• HES 130/0.42 significantly increased the risk of death or dependence
on dialysis at day 90, as compared with Ringer's acetate.
• HES 130/0.42 increased the absolute risk of death at 90 days by 8
percentage points, corresponding to a number needed to harm of
13.
• Similar results were observed in analyses adjusted for risk factors and
in the subgroups of patients with shock or acute kidney injury at the
time of randomization.

14. CHEST Trial: Hydroxyethyl starch or saline
for fluid resuscitation in intensive care.
• Crystalloid versus Hydroxyethyl Starch Trial (CHEST)
• Australian And New Zealand Intensive Care Society Clinical Trial Groups
• Published NEJM Nov 2012
• Multicentre, prospective, blinded, parallel-group, randomized, controlled
trial conducted in 32 hospitals in Australia and New Zealand conducted
between 2009 and
• 7000 patients intensive care patients who required fluid resuscitation over
and that required for maintenance or replacement fluids
• 3500 assigned to receive 6% HES (130/0.4) max dose of 50ml/kg day then open label
0.9% Saline
• 3500 patients assigned to receive 0.9% N/Saline

15. CHEST Trial: Hydroxyethyl starch or saline for fluid
resuscitation in intensive care - Conclusion
• There was no significant difference in mortality at 90 days in ICU
patients who received 6% HES (130/0.4) in 0.9% saline and those who
received 0.9% saline alone for fluid resuscitation.
• The effect on mortality did not differ significantly in six predefined
subgroup pairs: Acute Kidney Injury, Sepsis, Trauma, Traumatic Brian
injury, APACHE Score and receiving HES before Randomisation
• However more patients who received resuscitation with HES were
treated with renal-replacement therapy
• 6% HES does not have any clinical benefit compared with Saline in
ICU patients

16. Which Colloid?
• 4% albumin is generally safe
• Small advantage in Sepsis
• Except in trauma and head injuries
• Hydroxyethyl Starch
• No benefit over Normal Saline
• Increased mortality with Severe Sepsis
• More likely to require Renal Replacement
Therapy
• Gelofusin
• Modified Gelatine of bovine origin –
Succinylated
• Gelatine derivatives are mainly eliminated
unchanged through the kidney
• Produced in BSE-free countries
• No large RCTS

17. Which Crystalloid?
• Normal Saline is the default fluid for most situations
• Exceptions:
• Hartmann's for Burns
• Hypertonic Saline in Intracranial Hypertension
• Blood products in severe blood loss
• There is a move in intensive care to use of more physiological
crystalloids such as Hartmann's, lactated ringers and Plasma lyte
• Particularly in reducing hyperchloraemia and metabolic acidosis
• Diabetic Ketoacidosis – high risk
• However there is a distinct lack of high-level evidence with regards to
crystalloid choice

18. SPLIT Study: 0.9% saline vs. Plasma Lyte®
148 for fluid therapy in intensive care trial
• Australian and New Zealand Intensive Care Society Clinical Trials
Group
• The study hypothesis is that routinely using Plasma Lyte® 148 for fluid
therapy instead of 0.9% saline will reduce the risk of developing acute
kidney failure
• Pilot Randomised multicentre trial recruiting 2000 Patients
• In Progress

19. QUESTIONS?